This invention relates to agents for the treatment of diseases caused by parasitic protozoa. More particularly, the invention relates to agents for the treatment of Trypanosoma brucei brucei infections. T.b. brucei is the type organism of a group which causes African human and veterinary trypanosomiasis. These organisms include T. b. brucei, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. The invention further relates to compounds found to be active against a strain of Trichomonas vaginalis, and against Plasmodium falciparum, a causative agent of malaria, indicating a broader spectrum of antiprotozoal effects for the compounds of the invention.
The invention further relates to compounds for the treatment of malignant or neoplastic diseases.
Trypanosomiasis, or sleeping sickness, is a disease of widespread proportions which is endemic to Africa. One of the more promising developments in recent years, relating to the treatment of this disease as well as of malaria, has been the discovery that inhibitors of polyamine biosynthesis such as .alpha.-difluoromethylornithine (DFMO), E-2-fluoromethyldehydroornithine methyl ester, bis-benzyl polyamine analogs and most recently, MDL73811, an irreversible inhibitor of S-adenosylmethionine decarboxylase are highly effective agents for their treatment, as disclosed in the following literature:
C. J. Bacchi et al., Parasitic Protozoa and Polyamines, in Inhibition of Polyamine Metabolism, P. P. McCann, A. E. Pegg and A. Sjoerdsma, editors, Academic Press, Inc., Orlando, Fla. pp 317-344. PA1 A. J. Bitonti et al. Cure of Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense Infections in Mice with an Irreversible Inhibitor of S-Adenosylmethionine Decarboxylase. Antimicrob. Agents Chemother. 34, 1485, 1990. PA1 Trypanosoma brucei brucei (T. b. brucei) PA1 Plasmodium falciparum (P. falciparum) PA1 Trypanosoma brucei rhodesiense (T. b. rhodesiense) PA1 Trypanosoma brucei gambiense (T. b. gambiense) PA1 Trypanosoma cruzi PA1 Leishmania donovani PA1 Leishmania tropica PA1 Leishmania brasiliensis PA1 Trichomonas vaginalis PA1 Giardia lamblia PA1 Candida albicans PA1 Staphyloccus aureus PA1 Plasmodium falciparum
A. J. Bitonti et al. Bis(benzyl)polyamine Analogs Inhibit the Growth of Chloroquine-resistant Human Malaria Parasites in vitro and in Combination with .alpha.-Difluoromethylornithine Cure Murine Malaria. Proc. Natl. Acad. Sci., USA 86, 651 (1989) and
U.S. Pat. No. 4,914,086 discloses certain compounds that are useful in treating trypanosomiasis. While the compounds have the structure of nucleosides, their trypanocidal activity does not suggest the use of analogs of 5'-deoxy-5'-methylthioadenosine (MTA) because the biochemical activity is not related to polyamine metabolism. The disclosure of this patent is hereby incorporated by reference.
A further development in the field is disclosed in U.S. Pat. No. 4,820,692 which focuses on a group of thioribose compounds, but also discloses certain corresponding nucleosides. The ribose compounds are said to be analogs of 5-deoxy-5-methylthioribose (MTR) which have a variety of substituents R at the 5-position which can be H, Cl, F, Br, I or R.sub.1 S-- in which R.sub.1 is C.sub.1 -C.sub.10 linear or branched chain alkyl or halogenated C.sub.1 -C.sub.10 linear or branched chain alkyl. The preparation of the compounds where R is halogen or R.sub.1 is alkyl is disclosed. The thioribose compounds are disclosed to be useful as medicinal and biocidal agents in a selected number of pathogenic microorganisms, which have been shown to contain the enzyme 5-methylthioribose kinase (MTR kinase). Applicants have discovered a select few compounds disclosed in this patent that are unexpectedly useful in the treatment of diseases caused by 5'-deoxy-5'-methylthioadenosine (MTA) phosphorylase-containing microorganisms. This is in contrast to structurally similar compounds that are not useful in the treatment of such diseases. The preparation of Applicants' compounds is not disclosed in the patent. The use of compounds for the treatment of malignancies is not disclosed in the patent.
The compound 5'-deoxy-5'-(methylthio)adenosine (MTA), has well documented growth inhibitory activity although the exact mechanism of its growth inhibition remains obscure. Numerous analogs of MTA have been synthesized and investigated for their growth inhibitory and chemotherapeutic effects, such as disclosed by Montgomery et al., J. Med. Chem. 17, 1197, 1974, and Savarese et al. in Development of Target-Oriented Anticancer Drugs Y. C. Chang, ed., Raven Press, New York 1983, pp 129-142. The types of structural modifications which have been incorporated into MTA analogs include: 1) carbon for nitrogen replacements in the purine ring; 2) addition of exo-cyclic substituents on the purine ring, and 3) replacement of the 5'-methyl substituent of the ribose ring with numerous other alkyl or aryl substituents. As structurally modified analogs of a growth inhibitory cellular metabolite, the chemotherapeutic potential of these compounds has been explored. Of particular interest is a recent clinical study which has shown the promise of MTA, itself, as an agent for the treatment of topical disorders--most notably, venous ulcers, as disclosed by Tritapepe et al. in Acta Therapeutica 15, 299, 1989.
One aspect of the cellular biochemistry of MTA relates to the enzyme MTA phosphorylase. This enzyme catalyzes the degradation of MTA to adenine and 5-methylthioribose-1-phosphate (MTR-1-P). The degradation of MTA by MTA phosphorylase keeps cellular concentrations of MTA extremely low, thereby protecting the cell from the growth inhibitory effects of MTA. In 1978, Toohey first noted in Biochem. Biophys. Res. Commun. 87, 27, 1978, that some murine leukemia cell lines are devoid of MTA phosphorylase activity. Subsequently, clinical studies reported by Fitchen et al. at Cancer Res. 46, 5409, 1986, have found that MTA phosphorylase deficiency is found in a small but significant number of solid tumors and leukemias, with the greatest incidence among patients with acute lymphocytic leukemia of T cell origin as disclosed by Traweek et al. in Blood, 71, 1568, 1989. Since MTA phosphorylase has been detected in all non-neoplastic mammalian cells that have been examined, chemotherapeutic strategies which exploit this tumor specific deficiency in MTA phosphorylase, may be possible.
Savarese et al. have suggested that MTA analog substrates of MTA phosphorylase might be selectively cytotoxic, based on their ability to produce growth inhibitory metabolites of adenine and/or MTR-1-P which would interfere with the recycling of purines and/or of methionine. Among such cell types are those which have been designated as "methionine dependent" tumor cells by Hoffman in Anticancer Res. 5, 1, 1985. Methionine dependence is thus an additional tumor specific defect in methionine metabolism which can occur independent of, or in association with MTA phosphorylase deficiency.
It is a purpose of this invention to synthesize substrate analogs of MTA which would be activated by MTA phosphorylase to produce analogs of MTR-1-P which would interfere with methionine recycling, a process which could be selectively growth inhibitory in methionine dependent tumor cells or in other pathogenic microorganisms.